Benzo heterocyclic derivatives represented by the formula (1) shown below have excellent antibacterial activity and are useful as antibacterial agents (Japanese Examined Patent Publication No. 96557/1994). ##STR4##
In the formula, R.sup.2 is C.sub.1-6 alkyl. R.sup.3 is a 5- to 9-membered saturated or unsaturated heterocyclic ring residue, the heterocyclic ring residue optionally having one or more substituents. R.sup.4 is cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of C.sub.1-6 alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of C.sub.1-6 alkoxy, halogen and hydroxy on the phenyl ring; C.sub.1-6 alkyl which may be substituted by halogen, C.sub.2-6 alkanoyloxy or hydroxy; C.sub.2-6 alkenyl or thienyl. R is hydrogen or C.sub.1-6 alkyl.
More specifically, the benzo heterocyclic derivatives of the formula (1) and salts thereof have excellent antibacterial activities against various gram-positive bacteria and gram-negative bacteria and are useful for the treatment of various infectious diseases induced by various bacteria in human, other animals and fish and also useful as an external antimicrobial or disinfectant agent for medical instruments and the like. The benzo heterocyclic derivatives of the formula (1) and salts thereof show an excellent antibacterial activity against mycoplasma, Pseudomonas aeruginosa, anaerobic bacteria, resistant cells against various antibacterials, clinically isolated strains, and gram negative and gram positive bacteria such as Enterococcus faecalis and Staphyloccocus pyognes and hence are useful as an antibacterial agent for the treatment of diseases induced by these microorganisms. The benzo heterocyclic derivatives of the formula (1) and salts thereof show low toxicity and less side effect and have characteristic features such as good absorbability and sustained activity. Furthermore, the benzo heterocyclic derivatives of the formula (1) and salts thereof are useful for the treatment of urinary infectious diseases because they are highly excreted via urine, and further because of easy excretion via bile, they are useful for the treatment of intestinal infectious diseases.
According to Japanese Examined Patent Publication No. 96557/1994, the benzo heterocyclic derivatives of the formula (1) and salts thereof are prepared by using a fluoro benzoic acid of the formula (2) ##STR5##
wherein R.sup.2 is as defined above and R.sup.1 is halogen. PA1 wherein R.sup.1 is as defined above, R.sup.a is hydrogen or C.sub.1-6 alkyl, R.sup.b is C.sub.1-6 alkyl, and X.sup.1 is halogen. ##STR7## PA1 wherein R.sup.2 is as defined above and R.sup.c is C.sub.1-6 alkyl. PA1 wherein R.sup.d is alkyl. PA1 wherein R.sup.e is methyl or ethyl. PA1 wherein R.sup.1 is as defined above. The fluoro benzoic acid of the formula (3) is a compound which is unsubstituted at the 5-position with respect to the carboxyl group. PA1 wherein R.sup.1 and R.sup.2 are as defined above. The present invention has been accomplished based on the above findings. PA1 wherein R.sup.1 and R.sup.2 are as defined above, PA1 which comprises alkylating a fluoro benzoic acid of the formula (3) ##STR16## PA1 wherein R.sup.1 is as defined above. PA1 wherein R.sup.1 and R.sup.2 are as defined above, PA1 which comprises reducing a fluoro benzoic acid of the formula (4) ##STR18## PA1 wherein R.sup.1 and R.sup.2 are as defined above. PA1 wherein R.sup.1 and R.sup.2 are as defined above and M is a group of the formula: --MgX (wherein X is halogen), lithium metal or a group of the formula: ZnX (wherein X is as defined above). PA1 wherein R.sup.1 and R.sup.2 are as defined above. PA1 wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above, R.sup.5 is a group of the formula: --COR.sup.10 (wherein R.sup.10 is C.sub.1-6 alkyl) or --COOR.sup.11 (wherein R.sup.11 is hydrogen, C.sub.1-6 alkyl or a metal such as sodium, potassium, lithium, 1/2 magnesium or 1/2 zinc), R.sup.6 is C.sub.1-6 alkyl, R.sup.7 is a group of the formula: --NR.sup.12 R.sup.13 (wherein R.sup.12 and R.sup.13 are each C.sub.1-6 alkyl) or C.sub.1-6 alkoxy, X.sup.2 is halogen, and R.sup.8 and R.sup.9 are each C.sub.1-6 alkyl. PA1 wherein R.sup.2, R.sup.3, R.sup.4 and R are as defined above.
According to Japanese Examined Patent Publication No. 96557/1994, as shown below in Reaction Scheme A or B, a fluoro benzoic acid of the formula (2) is prepared by using known starting compounds by a multiple-step process comprising five steps. Thus according to the process described in Japanese Examined Patent Publication No. 96557/1994, a complicated reaction procedure must be carried out to prepare the fluoro benzoic acid of the formula (2). Furthermore, the desired fluoro benzoic acid of the formula (2) is obtained only in a low yield of about 8.3%. ##STR6##
Japanese Unexamined Patent Publications Nos. 243692/1990 and 74167/1992 and EP319906 disclose a process for preparing a fluoro benzoic acid of the formula (2) by using a compound of the formula (A), as shown in the following Reaction Scheme C: ##STR8##
The process, however, necessitates undertaking three steps to prepare the desired fluoro benzoic acid by using the compound of the formula (A). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 7.5%, based on the compound of the formula (A).
Japanese Unexamined Patent Publications Nos. 502452/1991 and 291959/1998 and J. Heterocyclic Chem., 27, p1610 (1990) disclose a process for preparing a fluoro benzoic acid of the formula (2) by using a compound of the formula (B), as shown in the following Reaction Scheme D: ##STR9##
The process, however, necessitates undertaking seven steps to prepare the desired fluoro benzoic acid by using the compound of the formula (B). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 45.8%, based on the compound of the formula (B).
J. Heterocyclic Chem., 27, p.1611 (1990) and Journal of Medicinal Chemistry, 1991, vol.34, No.3, p.1156 disclose a process for preparing a fluoro benzoic acid of the formula (2) by using the compound of the formula (C), as shown in the following Reaction Scheme E: ##STR10##
The process, however, necessitates undertaking four steps to prepare the desired fluoro benzoic acid by using the compound of the formula (C). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 25 to 30%, based on the compound of the formula (C).